The present invention relates to a method and apparatus for inducing a transient thermal gradient in human or animal tissue, and for obtaining thermal gradient spectra from the tissue as the thermal gradient propagates through the tissue. The resulting thermal gradient spectra can then be converted to conventional infrared spectra, which in turn can be used to determine concentrations of substances present in the tissue, such as glucose.
Millions of diabetics are forced to draw blood daily to determine their blood sugar levels. To alleviate the constant discomfort of these individuals, substantial effort has been expanded in the search for a non-invasive methodology to accurately determine blood glucose levels. Two patent applications, each assigned to Optiscan Biomedical Corporation of Alameda, Calif., have significantly advanced the state of the art of non-invasive blood glucose analysis. The methodology taught in U.S. patent application Ser. No. 08/820,378 is performed by the apparatus taught in U.S. patent application Ser. No. 08/816,723, and each of these references is herewith incorporated by reference.
By way of introduction, the methodology taught in U. S. patent application Ser. No. 08/820,378 is introduced as follows.
Any object at a temperature above absolute zero (xe2x88x92273.16 degrees Celsius) emits infrared energy. The energy density of such emissions is described by Planck""s law and are often referred to as a blackbody curves. Theoretically, a body with emissivity 1.0 would exhibit this emission spectra according to Planck""s Equation. Many objects have emissivities close to 1.0. Human tissue for instance has an emissivity of approximately 0.9 to 0.98. It is well known that infrared emissions from the human body obey Planck""s law and yield a black body type emission spectra.
Although a human body may emit energy that follows Planck""s Equation, Planck""s Equation does not completely describe the sum total of all energy emitted from a human body for two reasons:
1. The layers of the tissue and body fluids are selectively absorptive to some wavelengths of infrared energy. Thus, layers of tissue and blood or other fluids may selectively absorb energy emitted by the deeper layers before that energy can reach the surface of the skin.
2. There is a temperature gradient within a body, the deeper layers being warmer than the outer layers, which causes further deviation from the theoretical black body emissions.
Whenever these two conditions exist naturally, or can be forced to exist, the inventors have determined that a composition-dependent absorption spectra can be constructed from proper analysis of the total energy emitted from the body. For heterogeneous bodies, composition may be depth dependent and conversely, absorption spectra generated from deeper layers can contain sufficient composition information to allow quantification of the concentrations of individual constituents at that depth into the tissue. This is possible when a temperature gradient either occurs or is induced in the body. The slope of the temperature gradient is such that the temperature is cooler at the surface of the body closer to an infrared detector than at a more distant location from the detector, typically deep within the body.
The invention taught in U.S. patent application Ser. No. 08/820,378 uses the natural temperature within the body as the source of the infrared emissions. As will be explained in more detail below, as these deep infrared emissions pass through layers of tissue that are at a lower temperature than the deeper emitting layer, they are selectively self absorbed. This selective self-absorption produces bands of reduced energy in the resulting emission spectra when the energy finally exits the material under study. The spectra containing the bands where energy has been self absorbed is called an absorption spectra.
The invention taught in U.S. patent application Ser. No. 08/816,723 employs cooling to promote xe2x80x9cself-absorptionxe2x80x9d by letting the temperature gradient propagate to selected layers typically between 40 and 150 microns below the surface. When the temperature gradient has sufficiently propagated, the techniques presented therein can non-invasively deliver absorption spectra of the tissue, blood, and interstitial fluid containing glucose. The inventions incorporated by reference can deliver precise information about the composition of individual layers deep within a heterogeneous body of material by measuring the absorption spectra at different times as a temperature gradient propagates from the surface to deep within the material under test.
According to Ser. No. 08/820,378, there is provided a spectrometer for the non-invasive generation and capture of thermal gradient spectra from human or animal tissue. The spectrometer includes an infrared transmissive thermal mass for inducing a transient temperature gradient in the tissue by means of conductive heat transfer with the tissue, and cooling means in operative combination with the thermal mass for cooling the thermal mass.
Also provided is an infrared sensor means for detecting infrared emissions emanating from the tissue as the transient temperature gradient progresses into the tissue, and for providing output signals proportional to the detected infrared emissions. Data capture means is provided for sampling the output signals received from the infrared sensor means as the transient temperature gradient progresses into the tissue.
The invention of Ser. No. 08/820,378 also provides a method for the non-invasive generation and capture of thermal gradient spectra from living tissue. The method comprises the steps of:
cooling an infrared transmissive mass;
placing the infrared transmissive mass into a conductive heat transfer relationship with the tissue, thereby generating a transient temperature gradient in the tissue;
detecting infrared emissions emanating from the tissue and passing through the infrared transmissive mass;
providing output signals proportional to the detected infrared emissions; and
sampling the output signals as the transient temperature gradient progresses into the tissue.
In one preferred embodiment taught in Ser. No. 08/816,723 a germanium cylinder, cooled to 0xc2x0 C., is brought into intermittent contact with the patient""s warm skin, and the resulting thermal gradients so formed are used to perform the methodology taught in Ser. No. 08/820,378. Skin warming, according to this invention, may be accomplished by simply allowing the patient""s skin to naturally re-warm between cooling contact. Alternatively, an external heat source in the form of a second, warmer germanium cylinder may be utilized to facilitate skin warming. The intermittent heating and cooling of the patient""s skin results in the creation of transient thermal gradients. In this manner, useful spectra are generated which in turn yield very good measurements of the patient""s blood glucose levels.
While the methodology taught in the incorporated references presents a significant advance in non-invasive glucose metrology, there exists room for further improvements.
One such improvement lies in the manner in which the data collected by the apparatus are manipulated. In the methodology taught in Ser. No. 08/820,378 a volts-to-watts radiometric calibration step is often required. To preclude this requirement, the teachings of U.S. Pat. No. 6,161,028 were developed; this patent is herewith incorporated by reference. The methodology taught therein takes advantage of the fact that by inducing a temperature gradient, a difference parameter between the signal at a reference wavelength and the signal of an analyte absorption wavelength may be detected. The frequency or magnitude or phase difference of this parameter may be used to determine analyte concentration. A further object of the invention taught therein is to provide a method of inducing intermittent temperature modulation and using the frequency, magnitude, or phase differences caused by analyte absorbance to determine analyte concentration. This intermittent temperature may be periodic or a periodic.
One improvement to the apparatus taught in Ser. No. 08/816,723 enables the methodology taught in U.S. Pat. No. 6,161,028 to be performed. To enable this latter methodology, a fairly rapid series of measurements is taken. While the non-solid-state apparatus taught in Ser. No. 08/816,723 is capable of cycle frequencies of 2 Hz, an apparatus which seeks to implement measurements based on phase differences can, with good effect, make use of much faster cycle frequencies. Faster cycle times equate to faster measurements, and less patient waiting time. An apparatus which enables faster repetitive measurements or cycle times will accordingly enable these advantages.
An additional advantage of the method taught in U.S. Pat. No. 6,161,028 is that by using a periodically modulated temperature gradient, surface skin effects may be measured and corrected for. Another improvement lies in the nature of the contact between the germanium cylinder and the patient t s skin. It is possible that some apparatus performing subsurface thermal gradient spectrometry may require more than one measurement cycle, or xe2x80x9cthumpxe2x80x9d. Where this requirement exists in an apparatus requiring intermittent contact between the patient""s skin and heat transfer cylinder one possible source of error exists in the nature of this contact. If several measurement cycles are required to effect an accurate measurement of blood glucose, it follows that the cylinder must be brought into contact with the skin several times. The problem is that each of such contacts tends to be slightly different. Slight differences in pressure at the skin/cylinder interface occur. The patient may move that portion of his or her body, for instance the arm, in contact with the apparatus. Muscular tension may change from reading to reading. Each of these factors, and perhaps others as well, tend to complicate the already complex nature of the contact between the skin and the cylinder. A significant improvement will result if these xe2x80x9crheological effectsxe2x80x9d can be controlled or standardized if not altogether eliminated.
Closely related to the rheological effect problems previously enumerated is the intermittent nature of the thermal/mechanical/optical interfaces occasioned by the intermittent nature of several of the thermal, mechanical, and optical elements of the apparatus taught in Ser. No. 08/816,723.
Yet another improvement could be made to the apparatus taught in Ser. No. 08/816,723, which relates to a methodology which would perform at least one of the previously discussed subsurface thermal gradient spectrometric methodologies, and which could be reliably performed on an apparatus having no moving parts whereby the thermal gradient is generated and captured.
From the foregoing, advances in the field of non-invasive analyte determinations may be had by an apparatus which supports the methodology taught in U.S. Pat. No. 6,161,028, as well as other subsurface thermal gradient spectrometric methodologies including but not necessarily limited to those discussed in U.S. patent application Ser. Nos. 08/820,378 and 08/816,723. An apparatus which enabled more rapid measurement cycle times would not only do much to support the new methodology, but would lessen patient waiting time and improve measurement accuracy. One possible methodology which could provide such advantages would be to form a measuring device which does not rely on a mechanically intermittent device, such as the one taught in U.S. patent application Ser. No. 08/816,723 but which generates transient thermal gradients in a xe2x80x9csolid statexe2x80x9d manner: i.e., without the mechanical moving of a cooling/measuring cylinder into and out of contact with the patient""s skin. Such a solid state device would present the further advantages of leaving intact the thermal, mechanical, and optical interfaces intact, minimizing the rheological effects of intermittent cylinder/skin contact.
Such a system, however, poses a very difficult problem: If the device is left in intimate contact with the patient""s skin, it naturally follows that the same element will be used to both cool the skin and to take readings from it. Moreover, to increase cycle times, it may be necessary to provide an external warming to the skin. From this it follows that the same structure will be required to alternately warm the skin, cool the skin, and measure the thermal gradient so induced. Given that the element must perform each of these functions, the cool cylinder must be protected from unwanted warming. The warming function must be performed accurately without undue influence from the cooling function. Finally, could either be performed while measuring the transient thermal gradients so generated?
The present invention teaches a solid state non-invasive infrared absorption spectrometer for the generation and capture of thermal gradient spectra from living tissue. As used herein, the term xe2x80x9csolid statexe2x80x9d is defined to mean that the apparatus has no moving parts which move with respect to one another to effect the creation of the transient thermal gradient, or which affect the infrared spectroscopic measurement taken in response to the creation of such a gradient. Moreover, a solid state system is one in which the thermal gradient-inducing device is brought into contact with the patient""s arm, and left in such contact during the entire measurement series. To achieve the novel advantages obtainable from such a solid state device, the spectrometer includes an infrared transmissive thermal mass, or window, for inducing a transient temperature gradient in the tissue.
In place of the intermittent physical contact taught by U.S. patent application Ser. No. 08/816,723, the present invention utilizes a single thermal mass structure, referred to as a thermal mass window, which not only heats and cools the patient""s skin to affect the transient thermal gradient, but through which are also transmitted the absorption spectra generated by the gradient. Accordingly, the thermal mass window of the present invention remains in contact with the patient""s skin during the time the measurement is made, thereby minimizing intermittent rheological factors.
The thermal mass window includes an infrared transparent window in operative combination with an intermittent heat exchanger for intermittently inputting heat into the window. The thermal mass window is urged into contact with the patient""s skin and is thus utilized to conductively and intermittently cool and warm the patient""s skin. The cooling function may be implemented solely by the relatively large, cool thermal mass of the thermal mass window itself. Alternatively, heat can actively be withdrawn from the window by means of a cooling device which intermittently removes heat from the window. The cooling device may be a separate unit from the heat exchanger, or may be incorporated therewith. This intermittent warming and cooling of the skin may be periodic or a periodic.
In one embodiment of the present invention, the thermal mass window is implemented to include a plurality of zones disposed in or on the thermal mass window. In this embodiment the thermal mass window includes a first zone characterized by high thermal conductivity for cooling the thermal mass and hence the patient""s skin, and a second zone characterized by high thermal conductivity in operative combination with the first zone of high thermal conductivity, which second zone provides conductive heat transfer with the patient""s skin. The second zone is preferably of relatively small thermal mass, while the first zone is preferably of relatively large thermal mass. The present invention teaches a number of methodologies for forming the thermal mass window. Each of the zones is optically transparent in the infrared.
One methodology incorporates a third zone characterized by low thermal conductivity which is disposed between the first and second zones, which third zone serves to thermally isolate the first and second zones from one another. Indeed, this third zone can be said to be a thermal impedance zone. The third zone, like the first and second zones, is optically transparent in the infrared. And like the second zone, it is preferably, but not necessarily, of small thermal mass.
Disposed on an outer surface of the second zone is a heater for evenly and accurately heating the patient""s skin. The first zone may be in substantial thermal contact with a heat exchange body which, in combination with the mass of the first zone itself, serves to cool the entire thermal mass window. Accordingly, the present invention contemplates a window where heat is intermittently added to the second zone, and withdrawn from the first. The second zone serves to thermally isolate the first and third zones from one another. Each of the zones, being optically transparent, at least in the infrared, enables optical transmission through the entire thermal mass window.
The device taught herein may incorporate a heat exchanger, or may have no heat exchanger at all. Where a heat exchanger body is implemented, it may be cooled actively or passively. In one embodiment of the present invention, active cooling is achieved by providing a flow of cooling water to the heat exchanger body. Of course, alternative active or passive cooling methodologies, well within the ability of one having ordinary skill in the art, could be implemented with equal facility. In another embodiment of the present invention, there is provided no heat exchanger. In this embodiment, the thermal mass window has sufficient thermal capacity or mass that the temperature of the device as it is cycled rises sufficiently slowly during the measurement cycle that the temperature rise over time can be compensated for. Research indicates that some such embodiments may function properly for several minutes before the temperature rise becomes uncontrollable.
Where a structure is maintained in contact with the ambient atmosphere at an artificially depressed temperature, condensation can be a problem. To alleviate this problem the housing surrounding the window and heat exchanger can be equipped with any of several methodologies to prevent condensation from forming on one or more of the relatively cool surfaces. In one embodiment of the present invention, there are provided at least one of an electro-thermal heater and a flow of dry purge gas to keep one or more surfaces of the window free of condensate. Alternative methodologies for the prevention of condensation, including the use of chemical surfactants, may with equal facility be implemented.
Also provided is an infrared sensor device for detecting infrared emissions emanating from the tissue as the transient thermal gradient progresses into the tissue, and for providing output signals proportional to the detected infrared emissions.
A data capture device is further provided for sampling the output signals received from the infrared sensor device as the transient temperature gradient progresses into the tissue.
Other features of the invention are disclosed or apparent in the section entitled xe2x80x9cBEST MODE OF CARRYING OUT THE INVENTIONxe2x80x9d.